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After her parents' divorce, her mother had a relationship with musician Stephen Stills.
After her television debut with her mother in the soap opera Days of Our Lives and a commercial for Playtex baby bottles at three and five months, respectively, Applegate made her film debut in the 1979 film, Jaws of Satan (or King Cobra) at the age of seven, followed by 1981's Beatlemania.
Applegate guest-starred on two episodes of Friends, in the ninth (2002) and tenth (2003) seasons, titled "The One with Rachel's Other Sister" and "The One Where Rachel's Sister Babysits" as Amy Green, Rachel Green's (Jennifer Aniston) sister.
She won the Primetime Emmy Award for Outstanding Guest Actress in a Comedy Series her performance in "The One with Rachel's Other Sister." On the silver screen, she portrayed TV anchorwoman Veronica Corningstone in the 2004 films Anchorman: The Legend of Ron Burgundy and the bonus film Wake Up, Ron Burgundy: The Lost Movie (an alternative film comprising alternate takes and deleted scenes and story elements).
Because of her injury, Applegate had to wear special shoes to prevent another incident, and in a 2013 interview said that because of what happened, she "actually can't dance anymore.
Applegate has had major roles in several films, including Don't Tell Mom the Babysitter's Dead (1991), The Big Hit (1998), The Sweetest Thing (2002), Grand Theft Parsons (2003), Anchorman: The Legend of Ron Burgundy (2004) and its sequel Anchorman 2: The Legend Continues (2013), Hall Pass (2011), Vacation (2015) and Bad Moms (2016).In 1987, Applegate played the role of the ditzy, sexually promiscuous daughter, Kelly Bundy, on the Fox Network's first sitcom, Married... She portrayed her character for 11 years (1987–97).While working on the series, Applegate was seen in Dance 'til Dawn (1988, NBC) and in Streets (1990), in which a teenaged drug addict is stalked by a psychotic police officer.In late April 2005, she also took part in the annual Broadway Cares’ Easter Bonnet Competition, being sawed in half by a magician in their Clearly Impossible sawing illusion.
Sweet Charity ended its Broadway run on December 31, 2005.
In 1986, Applegate won the role of Robin Kennedy (1986–87), a policeman's daughter, in the police drama series Heart of the City.